rs45517932
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_138694.4(PKHD1):c.5125C>T(p.Leu1709Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00598 in 1,614,206 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5125C>T | p.Leu1709Phe | missense_variant | Exon 32 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.5125C>T | p.Leu1709Phe | missense_variant | Exon 32 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00365 AC: 555AN: 152218Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00282 AC: 709AN: 251342Hom.: 3 AF XY: 0.00297 AC XY: 404AN XY: 135836
GnomAD4 exome AF: 0.00623 AC: 9103AN: 1461870Hom.: 42 Cov.: 34 AF XY: 0.00603 AC XY: 4387AN XY: 727238
GnomAD4 genome AF: 0.00364 AC: 554AN: 152336Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 240AN XY: 74490
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:1Benign:3
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not provided Uncertain:1Benign:2
PKHD1: BS2 -
BS1 -
This variant is associated with the following publications: (PMID: 24162162, 30809968, 19940839, 20413436, 16133180, 15805161, 15108277, 12874454, 12846734) -
not specified Benign:3
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Variant summary: PKHD1 c.5125C>T (p.Leu1709Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251342 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0028 vs 0.0071), allowing no conclusion about variant significance. However, this variant was observed in high allele frequency (as high as 1.5%) in healthy controls in multiple publications and classified as polymorphism (Rossetti_2003, Bergmann_2014, Sharp_2005, Losekoot_2005). c.5125C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Gunay-Aygun_2010, Denamur_2010, Bullich_2018). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four have classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at